NF-kappaB is a transcription factor that appears to be fundamentally involved in the appropriate regulated expression of genes for certain cytokines, the IL-2 receptor, and MHC class I and II proteins that function in cell activation and the immune response. IkappaB is an inhibitor protein that binds to NF-kappaB, thereby blocking its DNA binding activity and thus providing a potential feedback inhibition loop to down-regulate cell activation. Systemic lupus erythematosus (SLE), a prototype systemic autoimmune disease, is characterized by hyperactivity of lymphocytes and the presence of a plethora of other cellular immune abnormalities. These defects are somewhat transient and often affect receptors/cytokines that are regulated by NF-kappaB. Hence, a defect(s) in the expression of IkappaB could explain some of the immune abnormalities that have been described in SLE (e.g., the increase in IL- 2R expression on T and B cells). Our hypothesis, therefore, is that the IkappaB feedback mechanism is aberrant in SLE. We have obtained preliminary data that demonstrate a marked decrease in IkappaB's expression in T cells from SLE patients as compared to normal controls. Experiments in Aim 1 will characterize the expression of IkappaB and NF- kappaB in peripheral blood T cell subpopulations from patients with SLE and normal control subjects, with and without receptor/ligand-induced activation in vitro. Studies in Aim 2 will determine T cell IkappaB expression during different phases of SLE disease activity, in first degree relatives of patients with SLE, and in diseases and clinical situations other than SLE. Emphasis in Aim 3 is on quantitating IkappaB mRNA in T cells and on determining the rate of IkappaB protein turn over. This project is expected to further our understanding of the pathogenesis of SLE and may establish a foundation for new therapeutic approaches in this disorder.